U.S. patent number 6,037,178 [Application Number 08/678,101] was granted by the patent office on 2000-03-14 for method for quality control of an analyzing system.
This patent grant is currently assigned to AVL Medical Instruments AG. Invention is credited to Marco Jean-Pierre Leiner, James K. Tusa.
United States Patent |
6,037,178 |
Leiner , et al. |
March 14, 2000 |
**Please see images for:
( Certificate of Correction ) ** |
Method for quality control of an analyzing system
Abstract
Quality control of an analyzing system that includes a portable
analyzer with insertable single-use cartridges whose sample chamber
contains optical and/or electrochemical sensors is accomplished by
bringing the sensors in the single-use cartridge into contact, or
are in contact with, a calibrating and/or conditioning medium, the
calibrating and/or conditioning medium exhibiting chemical and/or
physical parameters which influence the characteristic of at least
one of the sensors. Just before a sample is measured, the sensors
are contacted with a quality control liquid which is identical with
the calibrating and/or conditioning medium within a predetermined
desired range of accuracy for the sample components to be measured,
as regards the chemical and/or physical parameters influencing the
characteristic of at least one sensor during calibration and/or
conditioning. The instantaneous control values obtained on the
basis of the calibration values are subsequently compared to known
target control values.
Inventors: |
Leiner; Marco Jean-Pierre
(Grax, AT), Tusa; James K. (Alpharetta, GA) |
Assignee: |
AVL Medical Instruments AG
(Schaffhausen, CH)
|
Family
ID: |
3509109 |
Appl.
No.: |
08/678,101 |
Filed: |
July 11, 1996 |
Foreign Application Priority Data
|
|
|
|
|
Jul 17, 1995 [AT] |
|
|
1215/95 |
|
Current U.S.
Class: |
436/50;
422/68.1 |
Current CPC
Class: |
G01N
33/492 (20130101); Y10T 436/115831 (20150115) |
Current International
Class: |
G01N
33/49 (20060101); G01N 33/487 (20060101); G01N
033/00 (); G01N 033/48 () |
Field of
Search: |
;436/50,465
;422/68.1 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
International Pat. Pub. WO 92 01928 to S. Cozzette et al. entitled
Method for Analytically Utilizing Microfabricated Sensors During
Wet-Up, dated Feb. 6, 1992. .
International Pat. Pub. WO 85/04719 to R. Baker et al. entitled
"Self-Calibrating Single-Use Sensing Device for Clinical Chemistry
Analyzer," dated Oct. 24, 1985..
|
Primary Examiner: Feisee; Lila
Assistant Examiner: Pak; Michael
Attorney, Agent or Firm: Watson Cole Grindle Watson,
P.L.L.C.
Claims
We claim:
1. Method for quality control of an analyzing system consisting of
a portable analyzer with insertable single-use cartridges whose
sample chamber contains at least one optical and/or electrochemical
ion sensor selected from the group consisting of pH, Li.sup.+,
K.sup.+, Na.sup.+, Mg.sup.++, Ca.sup.++ and Cl.sup.- sensors and at
least one optical and/or electrochemical gas sensor selected from
the group consisting of O.sub.2 and CO.sub.2 sensors, wherein said
sensors are stored in contact with a conditioning liquid,
comprising the steps of:
a) reading production-inherent characteristics of the individual
ion and gas sensors into the analyzer, or using already stored
characteristics, and inserting the cartridge into the analyzer;
b) replacing the conditioning liquid present in the sample chamber
by a gaseous calibrating medium, wherein residues of the
conditioning liquid remaining in ion-permeable layers of the ion
sensors are treated with the gaseous calibrating medium to thereby
form a calibrating liquid, and wherein the gaseous calibrating
medium contacts the gas sensors;
c) simultaneously detecting calibration signals of the ion and gas
sensors;
d) contacting the ion and gas sensors with a quality control
liquid, which, as regards those chemical and/or physical parameters
that influence the characteristic of at least one ion or gas sensor
during calibration or conditioning, is identical with the
conditioning liquid within a predetermined range of accuracy for
the sample components to be measured;
e) simultaneously detecting control signals of the sensors;
f) determining instantaneous control values for the individual
sensors with the use of the characteristics entered or stored in
the analyzer and the calibration and control signals detected in
steps c) and e);
g) comparing the instantaneous control values with known target
control values; and
h) subsequent to the process of quality control, employing the same
cartridge for sample measurement, if the instantaneous control
values are identical with the target control values within the
predetermined range of accuracy.
2. Method according to claim 1, wherein in step d) the sensors are
contacted immediately prior to sample measurement with a quality
control liquid whose CO.sub.2 /pH equilibrium curve and pH.sub.2 O
in a measuring range and at a given measuring temperature are
identical with the respective values of the conditioning liquid
within the predetermined range of accuracy for the sample
components to be measured.
3. Method according to claim 2, wherein the ionic strength of the
quality control liquid is identical with that of the conditioning
liquid in the measuring range and at a given pH, within the
predetermined range of accuracy for the sample components to be
measured.
4. Method according to claim 2, wherein the osmotic pressure of the
quality control liquid is identical with that of the conditioning
liquid within the predetermined range of accuracy for the sample
components to be measured.
5. Method for quality control of an analyzing system consisting of
a portable analyzer with insertable single-use cartridges whose
sample chamber contains at least one optical and/or electrochemical
ion sensor selected from the group consisting of pH, Li.sup.+,
K.sup.+, Na.sup.+, Mg.sup.++, Ca.sup.++ and Cl.sup.- sensors,
wherein said sensors are stored in contact with a conditioning
liquid, comprising the steps of:
a) reading production-inherent characteristics of the individual
ion sensors into the analyzer, or using already stored
characteristics, and inserting the cartridge into the analyzer;
b) replacing the conditioning liquid present in the sample chamber
by a gaseous calibrating medium, wherein any residues of the
conditioning liquid remaining in ion-permeable layers of the ion
sensors are treated with the gaseous calibrating medium to form a
calibrating liquid;
c) simultaneously detecting calibration signals of the ion
sensors;
d) contacting the ion sensors with a quality control liquid, which,
as regards those chemical and/or physical parameters that influence
the characteristic of at least one sensor during calibration or
conditioning, is identical with the conditioning liquid within a
predetermined range of accuracy for the sample components to be
measured;
e) simultaneously detecting control signals of the sensors;
f) determining instantaneous control values for the individual
sensors with the use of the characteristics entered or stored in
the analyzer and the calibration and control signals detected in
steps c) and e);
g) comparing the instantaneous control values with known target
control values; and
h) subsequent to the process of quality control, employing the same
cartridge for sample measurement, if the instantaneous control
values are identical with the target control values within the
predetermined range of accuracy.
6. Method according to claim 5, wherein in step d) the sensors are
contacted immediately prior to sample measurement with a quality
control liquid whose CO.sub.2 /pH equilibrium curve and pH.sub.2 O
in a measuring range and at a given measuring temperature are
identical with the respective values of the conditioning liquid
within the predetermined range of accuracy for the sample
components to be measured.
7. Method according to claim 6, wherein the ionic strength of the
quality control liquid is identical with that of the conditioning
liquid in a predetermined measuring range and at a given pH, within
the predetermined range of accuracy for the sample components to be
measured.
8. Method for quality control of an analyzing system consisting of
a portable analyzer with insertable single-use cartridges whose
sample chamber contains optical and/or electrochemical sensors,
wherein said sensors are dry-stored comprising the steps of:
a) reading production-inherent characteristics of the individual
sensors into the analyzer, or using already stored characteristics,
and inserting the cartridge into the analyzer;
b) subjecting the sensors to a calibrating liquid;
c) simultaneously detecting calibration signals of the sensors,
taking into account the time lapse between the primary contact of
the sensors and the calibrating liquid and the detection of the
calibration signals;
d) contacting the sensors with a quality control liquid, which, as
regards those chemical and/or physical parameters that influence
the characteristic of at least one sensor during calibration, is
identical with the calibrating liquid within a predetermined range
of accuracy for sample components to be measured;
e) simultaneously detecting control signals of the sensors taking
into account the time lapse between the primary contact of the
sensors and the calibrating liquid and the detection of the control
signals;
f) determining instantaneous control values for the individual
sensors from the characteristics entered or stored in the analyzer,
and the calibration and control signals detected in steps c) and
e);
g) comparing the instantaneous control values with known target
control values; and
h) subsequent to the process of quality control, employing the same
cartridge for sample measurement, if the instantaneous control
values are identical with the target control values within the
predetermined range of accuracy.
9. Method according to claim 8, wherein in step d) the sensors are
contacted immediately prior to sample measurement with a quality
control liquid whose CO.sub.2 /pH equilibrium curve and pH.sub.2 O
in a measuring range and at a given measuring temperature are
identical with the respective values of the calibrating liquid of
step b) within the predetermined range of accuracy for the sample
components to be measured.
10. Method according to claim 9, wherein the ionic strength of the
quality control liquid is identical with that of the calibrating
liquid in the measuring range and at a given pH, within the
predetermined range of accuracy for the sample components to be
measured.
11. Method according to claim 9, wherein the osmotic pressure of
the quality control liquid is identical with that of the
calibrating liquid within the predetermined range of accuracy for
the sample components to be measured.
12. Method according to claim 8, wherein in step d) a gas of known
composition for the purpose of separating the calibrating liquid
from the quality control liquid is added.
Description
BACKGROUND OF THE INVENTION
The present invention relates to a method for quality control of an
analyzing system that makes use of a portable analyzer with
insertable single-use cartridges whose sample chamber contains
optical and/or electrochemical sensors, in particular sensors which
are designed for determining clinically relevant parameters (pH,
pCO.sub.2, pO.sub.2), ions (e.g., Li.sup.+, Na.sup.+, K.sup.+,
Mg.sup.++, Ca.sup.++, Cl.sup.-), and enzyme substrates (e.g.,
glucose, lactate, urea) in biological fluids.
Following is a definition of some major technical terms of the
invention in order to facilitate comprehension.
Analyzer: Measuring instrument based on optical and/or
electrochemical sensors for measurement of samples (blood samples,
for instance).
Portable analyzer: Point-of-care measuring instrument based on
optical and/or electrochemical sensors. The sensors are
incorporated in single-use cartridges which are inserted into the
analyzer for sample measurement and discarded after the measuring
process.
Sensor: Optical or electrochemical measuring element determining
the concentration or partial pressure of at least one chemical
component dissolved in a fluid. Several sensors may be used for
simultaneous determination of the concentrations or partial
pressures of different chemical components.
Simultaneous measurement: The sensors of a sensor bank are
contacted with the medium to be measured (calibrating medium,
control liquid, sample) during one and the same step of the
process. Detection of the measuring signals need not take place
simultaneously.
Single-use cartridge: A part which may be brought into contact with
a portable analyzer by mechanical as well as electrical and/or
optical means, featuring at least one sample chamber and sensors
that are in at least indirect contact with this chamber. The
single-use cartridge is designed for measurement of a single
sample.
Conditioning: Temporary contact of the sensors with a given medium
in order to obtain a stable sensor characteristic. Upon contact
with aqueous or moist gaseous media, dry-stored sensors exhibit a
characteristic that is changing over time. A similar effect is
produced, in particular with sensors based on ion-permeable
materials, by the diffusion-induced exchange of chemical components
with aqueous media of different composition.
Sensor characteristic: Functional relationship between the
concentration (or partial pressure) of a chemical component
contained in an aqueous solution (independent variable) and the
magnitude of a measurable optical or electrical signal of an
optical or electrochemical sensor.
Calibration: Determination of the sensor characteristic.
One-point calibration: Calibration at an expected value of the
quantity to be measured. For the purpose of calibration the signal
must usually be obtained at two or more values of the quantity to
be measured. If the functional relationship described by the
characteristic is at least partially known, however, as in the
instance of batchwise determination during manufacture or
reproducible manufacturing, it will usually suffice to obtain the
signal at a single value of the quantity to be measured in order to
obtain complete calibration.
Calibrating medium, calibrating liquid: Aqueous solution or gaseous
mixture containing at least one chemical component to be determined
by means of a sensor bank, the concentration or gas partial
pressure of this component being known and corresponding to an
expected value of the respective chemical component(s) in the given
measuring situation.
Quality control: Simultaneous determination of the concentrations
of dissolved chemical substances and/or gas partial pressures of a
quality control liquid by means of a sensor bank (for example, a
single-use cartridge), and subsequent comparison of instantaneous
and target values.
Quality control liquid: Aqueous solution supplied in a container
(preferably made of glass) preferably impermeable to gases (such as
O.sub.2, CO.sub.2, N.sub.2), water, and chemical substances that
are soluble in aqueous systems, which is treated with a gas of
known composition and contains various chemical components of a
liquid specimen to be measured by means of a sensor bank, the
concentration of these components corresponding to an expected
value of the measurement variable in the given measuring
situation.
Specimen: Fluids (for example, biological fluids, such as whole
blood, serum, urine). Concentrations or gas partial pressures of
the components to be determined are essentially unknown.
Sample: Random sample of the specimen.
Sample measurement: Simultaneous determination of the
concentrations and/or gas partial pressures of the chemical
substances dissolved in a sample by means of a sensor bank (such as
a single-use cartridge).
In clinical laboratories various analyzers are used for in-vitro
analyses of biological fluids (blood, urine, plasma, serum). The
instruments mostly are based on electrochemical sensors which are
calibrated at one or more expected values of the quantities to be
measured, by means of liquid and gaseous calibrating media provided
in the instrument, before the actual measuring process takes place.
For calibration of the individual sensors, various liquid and
gaseous calibrating media are employed.
It is often necessary to check accuracy and reliability of such
measuring systems by means of quality control liquids. These
liquids are aqueous, saline, pH-buffered solutions treated with a
gas of known composition of O.sub.2 and CO.sub.2 and supplied in
sealed glass containers. These liquids may contain various
additives to increase gas solubility, tensides to increase
wettability, and biocides to prevent biological activities. Quality
control liquids preferably are used for simultaneous control of all
sensors contained in the instrument; their chemical composition is
distinct from that of the calibrating media used.
DESCRIPTION OF THE PRIOR ART
In contrast to the stationary analyzing equipment used in large
clinical laboratories, a number of portable analyzers (point of
care instruments) have become known (see EP 0 460 343 B1, U.S. Pat.
No. 5,080,865, WO92/01928, U.S. Pat. No. 5,288,646). They are based
on optical or electrochemical sensors incorporated in disposable
cartridges. Since a new cartridge is used for each analysis, the
requirements to be met by the sensors differ from those of the
stationary equipment. As only a single calibrating medium is used,
the sensor characteristics must be determined at least partly
during the manufacturing process, or must be otherwise known. The
characteristic data are fed into the analyzer prior to each
cartridge measurement, or they are stored in the analyzer. Due to
the cost-saving use of a single calibrating medium, calibration
takes place at a single expected value of the respective variable
(one-point calibration), simultaneously for all sensors contained
in the cartridge. As soon as a single-use cartridge has been
inserted into the portable analyzer, all sensors should be ready
for use without further conditioning measures.
Although conventional quality control liquids may be used with
disposable cartridges, the sensors cannot be employed for
subsequent sample measurement due to the diffusion-induced exchange
between chemical components of such control liquids and the
sensors, or rather, additional steps and measures are required in
such instances, which would lead to further expense.
Since there is a slow, diffusion-induced exchange of chemical
substances between the sensor materials (usually supplied as layer
structures) and the measuring media (calibrating medium, control
medium, sample), the chemical composition of the sensitive layers
will change. Due to changes in concentration, the sensor
characteristics will drift. Depending on the chemical composition,
duration of exposure and temperature of the media in contact with
the sensors, different measured results will be obtained, depending
on whether the specimen is measured after calibration or after
control measurement. As a consequence, known types of quality
control liquids or methods of quality control will be useful in
checking the reliability and accuracy of the analyzer, but not the
reliability and accuracy of a single-use cartridge and sensors
designed for measurement of the specimen.
In EP 0 226 593 B, for example, an analyzing system for measuring
blood samples is disclosed, in which a disposable cartridge is
provided. The cartridge comprises a first gas-impermeable container
for a calibrating solution A, and a second such container for a
calibrating solution B, the chemical characteristics of the two
calibrating solutions being distinct but known. The two calibrating
solutions serve for two-point calibration of the cartridge. No
provisions are made for quality control as defined above.
A self-calibrating single-use cartridge for a clinical analyzer is
described in WO 85/04719. The cartridge has a rotatable reservoir
with several chambers, one of which contains a calibrating liquid
and the other one a sample. By rotation of the reservoir the
individual chambers are connected to the actual measuring channel
one after the other, where the desired parameters for the
calibrating liquid and the sample are determined and subsequently
evaluated.
SUMMARY OF THE INVENTION
It is an object of the present invention to propose methods of
quality control and quality control liquids which will permit first
a control measurement and then measurement of a specimen by means
of one and the same single-use cartridge, in addition to providing
information on the reliability of the analyzer, or rather,
reliability and accuracy of the individual sensors contained in the
single-use cartridge.
In the invention this object is achieved by providing that the
sensors in the single-use cartridge are brought into contact, or
already be in contact with, a calibrating and/or conditioning
medium, the calibrating and/or conditioning medium exhibiting
chemical and/or physical parameters which influence the
characteristic of at least one of the sensors, and contacting the
sensors with a quality control liquid just before a sample is
measured, which quality control liquid is identical with the
calibrating and/or conditioning medium within the desired range of
accuracy for the sample components to be measured, as regards those
chemical and/or physical parameters influencing the characteristic
of at least one sensor during calibration and/or conditioning, and
further comprising the instantaneous control values obtained on the
basis of the calibration values with the known target control
values.
The object of the invention is further achieved by providing that
the sensors in the single-use cartridge be brought into contact, or
already be in contact, with a calibrating and/or conditioning
medium, and that the sensors be contacted prior to sample
measurement with a quality control liquid whose CO.sub.2 /pH
equilibrium curve and pH.sub.2 O in the interesting measuring range
and at a given measuring temperature be identical with the
respective values of the calibrating and/or conditioning medium
within the desired range of accuracy for the sample components to
be measured.
It will be an advantage if the ionic strength of the quality
control liquid is identical with that of the calibrating and/or
conditioning medium in the interesting measuring range and at a
given pH, within the desired range of accuracy for the sample
components to be measured, or if the osmotic pressure of the
quality control liquid is identical with that of the calibrating
medium and/or conditioning medium.
A quality control liquid of the invention is characterized by its
being identical with the calibrating and/or conditioning medium
within the desired range of accuracy for the sample components to
be measured, as regards those chemical or physical parameters which
influence the characteristic of the individual sensors during a
preceding calibrating or conditioning process.
The single-use cartridges may be equipped with any combination of
the sensors described below, permitting use of both the method and
quality control liquid of the invention.
pH Sensors
Optical sensors for determination of the pH value usually contain a
pH indicator, such as an organic acid or base, which is immobilized
in an ion-permeable, mostly hydrophilic polymer layer by covalent,
electrostatic, or adsorptive bonds. By ionic exchange (e.g.,
H.sup.+, or OH.sup.-) via ion-permeable materials the immobilized
pH indicators may be brought into at least indirect contact with a
sample (M. J. P. Leiner and O. S. Wolfbeis, "Fiber Optic
pH-Sensors", in O. S. Wolfbeis, "Fiber Optic Chemical Sensors and
Biosensors", CRC-Press, Boca Raton, 1991, Chapter 8). In dependence
of the pH value of the specimen (pH=-log(aH.sup.+)) a thermodynamic
equilibrium is established between protonated and deprotonated
forms of the pH indicator. From the concentration ratio of the two
forms, which is measured by optical methods, the pH value of the
specimen may be inferred.
Suitable electrochemical sensors for determination of pH are glass
electrodes, liquid membrane electrodes, antimony electrodes, field
effect transistors (ISFET), solid state systems (noble metal/noble
metal oxide systems, such as Ir/IrO.sub.2, and Pd/PdO.sub.2), and
redox systems.
CO.sub.2 Sensors
Optical sensors for determination of the CO.sub.2 partial pressure
of a liquid specimen usually consist of a reaction chamber built in
layers and an ion-impermeable, gas-permeable material separating
the reaction chamber from the specimen. The reaction chamber is
frequently identical with the indicator-carrying material of an
optical pH sensor. The reaction chamber further contains one or
more pH buffering agents, such as carbonates, phosphates, and/or
organic compounds featuring acid or basic reactions in aqueous
media. At a given temperature, water content and composition of the
buffering agents, the pH value of the reaction chamber exhibits a
characteristic dependence on pCO.sub.2 of the specimen.
Electrochemical sensors for determination of the CO.sub.2 partial
pressure often exhibit a layer structure essentially similar to
that of optical sensors. Instead of an optical pH indicator one of
the pH sensitive electrodes described above is employed for pH
measurement of the reaction chamber.
Since gas-permeable, ion-impermeable separating materials are also
permeable to water by isothermal distillation, an exchange of water
will take place between specimen chamber and reaction chamber, in
addition to the gas exchange. Water is picked up or given off if
the partial pressure of water vapor or osmotic pressure of the
reaction chamber is distinct from that of the medium in the
specimen chamber. The exchange process will enter into a state of
equilibrium only when the partial pressure of water vapor and/or
osmotic pressure of both chambers have assumed the same value.
O.sub.2 Sensors
Optical sensors for determination of the O.sub.2 partial pressure
of a liquid or gaseous specimen usually contain an optical O.sub.2
indicator which is immobilized in a preferably ion-impermeable
polymer layer by covalent, electrostatic, or adsorptive bonds. To
avoid optical interferences with the specimen, a second polymer
layer, which is filled with pigments and preferably is
ion-impermeable, often is used for the purpose of optical
decoupling of the specimen chamber from the polymer layer carrying
the indicator.
Electrochemical sensors for determination of the O.sub.2 partial
pressure of a liquid or gaseous specimen usually are amperometric
electrodes. The actual electrode arrangement is frequently
separated from the specimen chamber by an ion-impermeable,
gas-permeable separating material.
Ion Sensors
The relevant scientific literature describes various optical
recognition systems of various design for determination of the
concentrations (or activities) of inorganic cations or anions
(NH.sub.4.sup.+, Li.sup.+, K.sup.+, Na.sup.+, Mg.sup.++, Ca.sup.++,
Cl.sup.-). Depending on the recognition system the chemical
components are provided in ion-permeable polymer materials often
configured as layer structures.
Electrochemical sensors for determination of the concentrations or
activities of the inorganic cations or anions referred to above
usually are potentiometric measuring systems. The recognition
system is based on an ionophor which is physically dissolved in a
polymer material.
Substrate Sensors
Optical and electrochemical sensors for the purpose of determining
the concentrations of biological substances reacting with enzymes,
such as glucose, lactate, urea, which are described in the relevant
scientific literature, are based on recognition systems which
usually undergo a specific biochemical reaction with the substance
to be determined (substrate). Parallel to the enzymatic substrate
decomposition other substances, such as O.sub.2, H.sub.2 O.sub.2,
NH.sub.4.sup.+, H.sup.+ are consumed and/or formed. The latter may
be determined by means of the sensors described above.
To determine glucose concentration, for instance, an optical or
electrochemical O.sub.2 sensor is employed, which contains an
enzyme in addition to the other components (see above). By means of
O.sub.2 measurement it is possible to determine glucose
concentration in the specimen.
Reference Electrodes
Unlike optical sensors electrochemical measuring devices require a
reference element. In potentiometric electrodes the reference
electrode is often located in the specimen chamber, i.e., at a
distance from the actual measuring electrode. In an exemplary
variant of the invention the potentiometric reference electrode is
a metal electrode (e.g., Ag) which is in indirect contact with the
specimen chamber via an ion-permeable material. The ion-permeable
material contains the ionic components necessary for the
potential-building process (e.g., AgCL/KCl).
A liquid suitable for simultaneous calibration of several sensors
in a single-use cartridge contains the ionic and/or gaseous
components to be determined at known concentrations and/or partial
pressures corresponding to an expected value of the measurement
variable in the given measuring situation. A liquid of such
composition can also be used for conditioning of the sensors. As
the solubilities of the gaseous components (O.sub.2, CO.sub.2) in
aqueous liquids will strongly depend on temperature, and as there
is a diffusion-controlled, temperature-dependent gas exchange with
the plastic materials of the single-use cartridge, the gas partial
pressures of the calibrating liquid are not known with sufficient
accuracy at the time of calibration, in particular when the
temperature of the single-use cartridge is adjusted from storage
temperature (0-35.degree. C.) to measuring temperature (37.degree.
C.).
One possibility of obtaining more accurately known gas partial
pressures at the time of calibration is the use of a liquid
calibrating medium treated with calibrating gas in a separate
gas-impermeable container preferably integrated in the single-use
cartridge (WO 92/01928).
If the presence of two liquids (conditioning liquid and calibrating
liquid) in a single-use cartridge is to be avoided, the sensors in
a single-use cartridge must be dry-stored until calibration takes
place. By contact with liquid media (calibrating liquid, control
liquid, aqueous specimen) dry-stored sensors will slowly absorb
water (hydration, wet-up, conditioning). The kinetics of hydration
depends on different factors, such as temperature, pH, or
physico-chemical material properties. Since the sensor
characteristic depends on the state of hydration of the respective
sensors, it will vary continuously at a non-uniform rate. WO
92/01928 discloses computer-assisted methods for compensation of
such sensor signals varying monotonously with hydration
processes.
According to the invention, quality control of dry-stored sensors
is possible if the following steps are taken:
Production-inherent characteristics of the individual sensors are
read into the analyzer, or are already stored therein, and the
cartridge is inserted into the analyzer.
The sensors are subjected to a liquid calibrating medium.
The calibration signals of the sensors are detected simultaneously,
taking into account the time lapse between the primary contact of
the sensors and the calibrating liquid and the detection of the
calibration signals.
The sensors are contacted with a quality control liquid, with the
possible addition of a gas of known composition for the purpose of
separating the calibrating liquid from the quality control liquid,
which latter, as regards those chemical and/or physical parameters
that influence the characteristic of at least one sensor during
calibration, should be identical with the calibrating liquid within
the desired range of accuracy for the sample components to be
measured.
The control signals of the sensors are detected, taking into
account the time lapse between the primary contact of the sensors
and the calibrating liquid and the detection of the control
signals.
From the characteristics read into, or known by, the analyzer, and
the calibration and control signals detected simultaneously,
instantaneous control values are determined for the individual
sensors.
The instantaneous control values are compared with the known target
control values.
Subsequent to the process of quality control, the same cartridge is
employed for sample measurement, if the instantaneous control
values are identical with the target control values within the
desired range of accuracy.
Gas partial pressures which are known much more accurately at the
time of calibration may be obtained by treating the sensors stored
in contact with a liquid conditioning medium, with a calibrating
gas of known composition that is preferably provided in the
portable analyzer. Due to the preceding lengthy contact of the
sensors and the conditioning liquid, whose residues remaining in
the ion-permeable materials of any pH sensor provided, will supply
a calibrating medium for the pH sensor if treated with a CO.sub.2
-containing calibrating gas, the components exchangeable by
diffusion between the sensors and the liquid calibrating medium,
are in a state of chemical equilibrium. According to the invention
the method for quality control of sensors that are stored in
contact with a liquid conditioning medium is characterized by the
following steps:
Production-inherent characteristics of the individual sensors are
read into the analyzer, or are already stored therein, and the
cartridge is inserted into the analyzer.
The conditioning liquid present in the sample chamber is replaced
by a gaseous calibrating medium, any residues of the conditioning
liquid remaining in the sample chamber or in contact with
individual sensors being treated with the calibrating gas.
The calibration signals of the sensors are detected
simultaneously.
The calibrating gas is replaced by a quality control liquid, which,
as regards those chemical and/or physical parameters that influence
the characteristic of at least one sensor during calibration and/or
conditioning, should be identical with the calibrating liquid
and/or calibrating gas within the desired range of accuracy for the
sample components to be measured.
The control signals of the sensors are detected simultaneously.
With the use of the characteristics read into or known by the
analyzer and the calibration and control signals detected
simultaneously, instantaneous control values are determined for the
individual sensors.
The instantaneous control values are compared with the known target
control values.
Subsequent to the process of quality control the same cartridge is
employed for sample measurement, if the instantaneous control
values are identical with the target control values within the
desired range of accuracy.
Due to the variable concentrations of the electrolytes exchangeable
between calibrating liquid, control liquid, or specimen and a
reference electrode, a diffusion potential will arise at the phase
interface of potentiometric reference electrodes. If the respective
electrolyte concentrations are known in both phases, the diffusion
potential may be calculated and its effect on the measured result
taken into consideration. With given materials the kinetics of the
exchange process will depend on the temperature, the concentration
gradients of the electrolytes, and the physical properties of the
materials used. At a given time after contact with saline solutions
the diffusion potential may be calculated in dependence of
temperature and the duration of contact.
As regards the sensors used in this context, it should be noted
that low-molecular molecules that are preferably uncharged will
slowly diffuse through ion-permeable as well as ion-impermeable
sensor materials, and may influence the sensor characteristic of
optical and electrochemical sensors by changing the chemical and/or
physical material properties and interacting with chemical
recognition systems.
Preferably low-molecular, electrically charged molecules (ions)
usually will diffuse freely through hydrophilic polymer materials
(hydrogels), changing the sensor characteristic of suitably
structured sensors (e.g., optical pH sensors, optical ion sensors,
optical and electrochemical substrate sensors).
The exchange processes will reach a state of equilibrium only when
the chemical potentials of the substances to be exchanged are in
balance. Although it is principally possible to compute the sensor
characteristic prevailing at a given time from the known duration
and temperature of the contact with liquid media, this method is
quite inaccurate, especially for sequential contact with fluids of
different compositions (calibration liquid, control liquid,
specimen). Use of the quality control liquid according to the
invention will prevent the above disadvantages.
An ideal quality control liquid for sensors in a single-use
cartridge would have the same composition as the calibrating liquid
(in substantially dry-stored sensors), or as the residues of the
conditioning liquid remaining in the sensor materials (in
wet-stored sensors). The demands to be met by a quality control
liquid according to the invention will only have to satisfy the
criteria laid down in the patent claims, however, as
(1) small amounts of certain additives have no significant
influence on the measuring properties of the sensors;
(2) in the instance of substrate sensors (e.g., glucose sensors)
the calibrating liquid, for example, contains no substrate, whereas
the quality control liquid should have a substrate concentration
corresponding to the expected value of substrate concentration;
(3) for checking of the ion sensors different relative
concentrations of cations (Na.sup.+, K.sup.+, . . . ) are possible,
and only the same total ionic strength is required.
The control liquid according to the invention has the following
characteristics:
(1) In the interesting measuring range (pCO.sub.2 10-120 torr, pH
6.8-8.0) and at a given measuring temperature (20-40.degree. C.),
the CO.sub.2 /pH equilibrium curve (pH=f(pCO.sub.2, T,
concentrations of pH buffer components, ionic strength)) (see also
"The Acid-Base Status of the Blood, Siggaard-Anderson, Munksgaard,
Copenhagen 1974; or "pH-Wert Berechnung", C. Bliefert, Verlag
Chemie Weinheim, New York 1978) of the quality control liquid is
identical with that of the calibrating liquid or conditioning
liquid within the desired range of accuracy (see FIG. 3).
(2) In the instance of optical pH and ion sensors, especially, the
ionic strength of the control liquid should be the same as that of
the control liquid or conditioning liquid in the interesting
measuring range and at given pH.
(3) The quality control liquid may have any convenient pCO2 or/and
pO.sub.2, for example, in the interesting measuring range. The gas
partial pressures Of pCO.sub.2 and pO.sub.2 may differ from those
of the calibrating liquid or the conditioning liquid and the
calibrating gas.
Single-use cartridges that are suitable for use with the method of
the invention are described in EP 0 460 343 B1 referred to above,
for example.
BRIEF DESCRIPTION OF THE DRAWINGS
Furthermore, the variant of a single-use cartridge shown in FIGS. 1
and 2 of the present invention may be used,
FIG. 1 giving a view of the cartridge from above, and
FIG. 2 a section along line II--II in FIG. 1.
FIG. 3 depicts a CO.sub.2 /pH equilibrium curve for an embodiment
of a calibrating and conditioning media for use in the cartridge of
FIGS. 1 and 2.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The cartridge substantially comprises an upper part 1 and a lower
part 2 which are combined to form a U-shaped sample channel 3. The
sample channel 3 contains sensors 4, for example, for measurement
of pH, CO.sub.2, O.sub.2. For control of the different media a
rotatable valve 5 is placed in a cup-shaped receptacle 6 moulded
integral with the lower part 2, whose axis 7 is normal to the plane
defined by the two legs of the sample channel 3. Inside the valve 5
configured as a hollow cylinder a waste container is provided to
collect the conditioning liquids, calibrating media, quality
control liquid, and the sample, if necessary. In the instance of
dry-stored sensors the waste container 8 of the valve 5 may be used
for storage of the calibrating liquid before the measuring
process.
Suitable sensors for use with the method of the invention are
optical or electrochemical sensors for pH, pO.sub.2, pCO.sub.2,
Li.sup.+, Na.sup.+, K.sup.+, Mg.sup.+, Ca.sup.++, Cl.sup.-,
glucose, lactate, urea (BUN), uric acid, creatinine,
cholesterol.
As regards the composition of a conditioning liquid or a
calibrating liquid for implementation of the method of quality
control according to the invention, the following aspects should be
considered;
If a pH measuring element is used: One-point calibration of pH
measuring elements for biological fluids, such as whole blood, is
conveniently performed at values in the physiologically normal pH
range (7.35-7.45). To obtain these values, suitable chemical
components of aqueous solutions are used, such as phosphates,
organic zwitterionic compounds, e.g., HEPES, MOPS, TES (described
in Good et al., Biochemistry 5, 467-477, 1996), and organic
N-containing bases, such as TRIS.
Exemplary liquid: Water containing 0.008695 mol/kg KH2PO4 and
0.03043 mol/kg Na.sub.2 PO.sub.4 in solubilized form, exhibits an
ionic strength of 0.100 mol/kg and a pH of 7.385 at 37.degree. C.
in the absence of CO.sub.2.
Adjustment of ionic strength: As the sensor characteristic of
optical pH measuring elements in particular will depend on the
ionic strength of liquid measuring media, the ionic strength of the
conditioning or calibrating solution should be adjusted to the type
of specimen being measured. Values of the ionic strength of whole
blood are 0.130-0.170 mol/l, approximately.
For adjustment of the ionic strength salts which react neutral in
aqueous solution may be added to the conditioning liquid or
calibrating liquid. Suitable substances include all saline
compounds of strong acids and strong bases that are soluble in
aqueous environment, such as NaCl, KCl, LiCl, Na.sub.2 SO.sub.4,
NaNO.sub.3, or salts of weak acids and weak bases (e.g., CH.sub.3
COOLi), if supplied in the interesting pH measuring range in
dissociated or protonated form. Since such anions and cations could
also be counterions of pH buffer components, the concentrations of
all components must be adjusted correspondingly.
If pH and CO.sub.2 measuring elements are used: For simultaneous
one-point calibration of a CO.sub.2 sensor provided in a single-use
cartridge for blood gas analysis it will be an advantage if the
liquid is subject to a CO.sub.2 partial pressure in the
physiologically normal range (35-45 torr, approx.). By application
of 40 torr CO.sub.2 the pH value referred to above will drop to
6.961 at an ionic strength of 0.092 mol/l. After the addition of
0.024 mol/l NaHCO.sub.3 the pH will rise again to 7.385 at an ionic
strength of 0.124 mol/l.
If O.sub.2 measuring elements are used: For simultaneous one-point
calibration of an O.sub.2 sensor provided in a single-use cartridge
it will be an advantage if the calibrating medium has a pO.sub.2 in
the physiologically normal range (90-110 torr, approx.). The ions
of aqueous media usually have no influence on such sensors, whereas
pH.sub.2 O or osmotic pressure do influence them.
If ion sensors are used: For simultaneous one-point calibration of
ion sensors additionally provided in a single-use cartridge (for
example, for Li.sup.+, Na.sup.+, K.sup.+, Mg.sup.++, Ca.sup.++,
Cl.sup.-) it will be a special advantage if the concentrations (or
activities) of the respective cations and anions are adjusted to
normal values of the specimen. Normal values of whole blood, for
instance, are in the range of 135-150 mmol/l for Na.sup.+, 3.5-5.0
mmol/l for K.sup.+, 1.0-1.4 mmol/l for Ca.sup.++, 98.0.sup.- 119.0
mmol/l for Cl.sup.-.
Exemplary Calibrating and Conditioning Media
If the single-use cartridge contains sensors for determination of
pH, pCO.sub.2 and pO.sub.2, and the K.sup.+, Na.sup.+, and Cl.sup.-
concentrations of whole blood, for example, an aqueous solution
subject to 40 torr CO.sub.2, 90 torr O.sub.2 at 37.degree. C., of
the composition indicated below,
______________________________________ Na+ K+ Cl- ionic strength
Component (mol/1) (mol/1) (mol/1) (mol/1) (mol/1)
______________________________________ NaH2PO4 0.0028 0.0028 0.0028
Na2HPO4 0.0112 0.0224 0.0336 NaHCO3 0.0243 0.0243 0.0243 NaCl
0.0960 0.0960 0.0960 0.0960 KCl 0.0040 0.0040 0.0040 0.0040 Totals
0.1455 0.0040 0.1000 0.1607
______________________________________
will fulfill the above requirements. The liquid has a pH of 7.385
(see FIG. 3, line X), ionic strength of 160 mmol/l, Na+
concentration of 145 mmol/l, K.sup.+ concentration of 4 mmol/l, and
Cl.sup.- concentration of 100 mmol/l.
The CO.sub.2 /pH equilibrium curve of this liquid is indicated in
FIG. 3.
Tensides: Prolonged contact of the sensors with a conditioning
liquid will lead to increased formation of bubbles. The presence of
bubbles in the measuring device will make it more difficult to
replace liquids by gaseous media. To avoid bubbling and improve
wettability it is advantageous to add small quantities of tensides.
(Examples: Triton X100: Du Pont Company, 549 Albany Str., Boston,
Mass. 02118, USA; Dehydron 241, Dehydrol 100: Henkel Corporation,
300 Brookside Ave., Ambier, Pa. 19002, USA).
Biocides: Biological activities frequently lead to a change in the
composition of aqueous solutions, in particular, a change in pH.
Due to these activities pH is not known with sufficient accuracy at
calibration or at the time of control measurement. For this reason
it is recommended to add small quantities of biocides to the
liquids. (Examples: NaN.sub.3, Mergal K9N: manufactured by Riedel
de Haan AG, marketed through Hoechst Austria AG, A-1121 Vienna,
Austria; Proclin 300, Proclin 150: Supelco, Inc., Supelco Park,
Bellefonte, Pa. 16823, USA; Bronidox L: Henkel Corporation, 1301
Jefferson Str., Hoboken, N.J. 07030, USA; Nuosept C: Huls America,
Inc., Turner Place, P.O.Box 365, Piscataway, N.J. 08855).
Gas solubility: Further substances may be added to liquid
calibrating media in order to increase gas solubility (for example,
fluorocarbons for an increase of oxygen solubility).
Following is an example for the composition of a quality control
liquid for implementation of the method according to the
invention.
A suitable quality control liquid exhibits the parameters to be
determined by means of the sensors in a single-use cartridge at
concentrations or partial pressures identical with the respective
expected values of the specimen. Preferably, the values of these
parameters are identical with those of the calibrating liquid.
The control liquid is treated with a gas of known O.sub.2 and
CO.sub.2 composition and is stored before use in a gas and water
impermeable container (preferably a glass ampoule). The relative
composition of the treated gaseous mixture may deviate from that of
the conditioning or calibrating liquid.
The exemplary conditioning or calibrating liquid referred to above
(see Table page 29) also is suited as quality control liquid. Since
the quality control liquid is identical with the conditioning or
calibrating liquid, all physical and chemical parameters will
naturally be the same. It should be noted that a quality control
liquid according to the invention need only be in accordance with
those physical and/or chemical parameters which influence the
sensor characteristic within the desired range of accuracy for the
sample components to be measured.
It will thus suffice if the quality control liquid for use with the
method of the invention is identical with the calibrating liquid
and/or conditioning liquid as regards CO.sub.2 /pH equilibrium
curve and ionic strength.
In the instance of sensors with ion-impermeable separating
membranes, it is further recommended that the water vapor partial
pressure of the control liquid be the same as that of the
calibrating and/or conditioning liquid.
If further chemical additives are used the influences of their
chemical parameters on the physical quantities referred to above
must be taken into account.
With biological specimens (e.g., whole blood), in particular, it is
often necessary to provide control values above and below the
physiologically normal range of the respective measurement
quantities, in addition to the control values inside this
range.
For example, if the above quality control liquid is subject to 65
torr CO.sub.2 and 60 torr O.sub.2 at 37.degree. C., the composition
of the pH buffer components will change, while the concentrations
of the cations and anions of saline compounds of strong acids with
strong bases (Na.sup.+, K.sup.+, Cl.sup.-) that are soluble in
aqueous environment, will remain the same:
______________________________________ Na+ K+ Cl- ionic strength
Component (mol/l) (mol/l) (mol/l) (mol/l) (mol/l)
______________________________________ NaH2PO4 0.0039 0.0039 0.0039
Na2HPO4 0.0100 0.0200 0.0300 NaHCO3 0.0255 0.0255 0.0255 NaCl
0.0960 0.0960 0.0960 0.0960 KCl 0.0040 0.0040 0.0040 0.0040 Totals
0.1454 0.0040 0.1000 0.1594
______________________________________
The pH value is 7.191 (see FIG. 3, line Y). The CO.sub.2 /pH
equilibrium curve remains the same. Within the desired measuring
accuracy for the sample components to be measured the ionic
strength will thus remain unchanged.
If additional control values for ion sensors are to be determined
outside of the respective physiologically normal ranges, the
concentrations of the neutral salts added may be modified. Since
changes in the concentrations of the neutral salts will influence
ionic strength, it is possible for the purpose of adjusting the
ionic strength to that of the conditioning or calibrating liquid,
to add yet another neutral salt whose anionic or cationic
components differ from the sample parameters to be determined
(e.g., Li.sub.2 SO.sub.4, LiNO.sub.3, CH.sub.3 COOLi).
______________________________________ Na+ K+ Cl- ionic strength
Component (mol/l) (mol/l) (mol/l) (mol/l) (mol/l)
______________________________________ NaH2PO4 0.0039 0.0039 0.0039
Na2HPO4 0.0100 0.0200 0.0300 NaHCO3 0.0255 0.0255 0.0255 NaCl
0.0660 0.0660 0.0660 0.0660 KCl 0.0060 0.0060 0.0060 0.0060 LiNO3
0.0280 0.0280 Totals 0.1154 0.0060 0.0720 0.1594
______________________________________
The liquid has a pH of 7.191. All exemplary sample parameters to be
determined are outside of the physiologically normal range of whole
blood. Nevertheless, CO.sub.2 /pH equilibrium curve and ionic
strength remain unchanged (see FIG. 3, line Y).
The measuring process for use with wet-stored sensors (e.g., EP 0
460 343 B1) comprises the following steps:
Preparation of Cartridge & Conditioning
1. The sample chamber (sample channel) is filled once or repeatedly
with conditioning liquid and closed afterwards.
2. The single-use cartridge is packaged in a gas and water
impermeable container and stored until use. (Conditioning of the
sensors may take place after filling of the measuring chamber or
during storage).
3. The cartridge is removed from the package, the sensor
characteristics are read into the measuring instrument, and the
cartridge is inserted into the portable analyzer.
Calibration Measurement
4. The conditioning liquid in the sample chamber (sample channel)
is displaced by a calibrating gas into a waste container(integrated
in the cartridge, for example). Residues of the conditioning liquid
will remain in the ion-permeable layers of the sensors and are
subject to the calibrating gas together with the sensor
materials.
5. The calibration signals of the different sensors are detected
simultaneously.
Control Measurement
6. The calibrating gas is replaced by a quality control liquid
according to the invention, which is supplied in a gas and water
impermeable (glass) container.
7. The control signals of the different sensors are detected
simultaneously.
8. The instantaneous control values (pH, concentrations/gas partial
pressures) are determined, taking into account the sensor
characteristics entered, the calibration signals detected (step 5)
and the control signals detected (step 7). The instantaneous
control values are subsequently displayed.
9. The instantaneous control values obtained in step 8 are compared
with the known target control values, the differences in these
values providing information on the accuracy and reliability of the
portable analyzer, or rather, the cartridge.
Sample Measurement
10. The quality control liquid in the sample chamber (sample
channel) is displaced by means of a calibrating gas into a waste
container (integrated in the cartridge, for example).
11. The calibrating gas is replaced by the specimen (for example,
blood).
12. The specimen signals of the different sensors are detected
simultaneously.
13. The measurement variables (pH, concentrations/gas partial
pressures) are determined, taking into account the sensor
characteristics entered, the calibration signals detected (step 5),
and the specimen signals detected (step 12). The measured
quantities are subsequently displayed.
The measuring process for use with dry-stored sensors (e.g., WO
92/01928) comprises the following steps:
Preparation of Cartridge
1. A gas and water impermeable reservoir preferably contained in
the single-use cartridge is filled with calibrating liquid and
closed afterwards.
2. The cartridge is packaged in a gas and water impermeable
container and stored until use.
3. The cartridge is removed from the package, the sensor
characteristics are read into the measuring instrument, and the
cartridge is inserted into the portable analyzer.
Calibration Measurement
4. A connection is established between the reservoir and the sample
chamber (sample channel). The calibrating liquid in the reservoir
is transferred into the sample chamber (sample channel).
5. The calibration signals of the different sensors are detected
simultaneously, taking into account the time of signal detection
relative to the time of primary contact with the calibrating
liquid.
Control Measurement
6. The calibrating liquid in the sample chamber (sample channel) is
replaced by a gaseous medium of known composition (ambient air,
among others). The gaseous medium in the sample chamber (sample
channel) is replaced by a quality control liquid according to the
invention, which is supplied in a gas and water impermeable (glass)
container.
7. The control signals of the different sensors are detected
simultaneously, taking into account the time of signal detection
relative to the time of primary contact with the calibrating
liquid.
8. The instantaneous control values (pH, concentrations/gas partial
pressures) are determined, taking into account the sensor
characteristics entered, the time of detection of the specimen
signals relative to the time of primary contact with the
calibrating liquid, the calibration signals detected (step 5) and
the control signals detected (step 7).
9. The instantaneous control values obtained in step 8 are compared
with the known target control values, the differences in these
values providing information on the accuracy and reliability of the
portable analyzer, or rather, the cartridge.
Sample Measurement
10. The quality control liquid in the sample chamber (sample
channel) is replaced by a gaseous medium of known composition
(ambient air, for example), and transferred into a waste container
(integrated in the cartridge, for example).
11. The gaseous medium in the sample chamber (sample channel) is
replaced by the specimen (for example, blood).
12. The specimen signals of the different sensors are detected
simultaneously, taking into account the time of signal detection
relative to the time of primary contact with the calibrating
liquid.
13. The measurement variables (pH, concentrations/gas partial
pressures) are detected and displayed, taking into account the
sensor characteristics entered, the time of specimen signal
detection relative to the time of primary contact with the
calibrating liquid, the calibration signals detected (step 5), and
the specimen signals detected (step 12). The measured quantities
are subsequently displayed.
* * * * *